BLM promotes the activation of Fanconi Anemia signaling pathway
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Jayabal Panneerselvam1, Hong Wang2,3, Jun Zhang2, Raymond Che1, Herbert Yu1, Peiwen Fei1
1University of Hawaii Cancer Center, University of Hawaii, Honolulu, HI, USA
2Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
3Current address: Sun Yat-Sen University, Guangzhou, China
Peiwen Fei, email: [email protected]
Keywords: Fanconi Anemia, BLM, FANCD2 monoubiquitination, DNA damage, tumorigenesis
Received: October 25, 2015 Accepted: March 28, 2016 Published: April 12, 2016
Mutations in the human RecQ helicase, BLM, causes Bloom Syndrome, which is a rare autosomal recessive disorder and characterized by genomic instability and an increased risk of cancer. Fanconi Anemia (FA), resulting from mutations in any of the 19 known FA genes and those yet to be known, is also characterized by chromosomal instability and a high incidence of cancer. BLM helicase and FA proteins, therefore, may work in a common tumor-suppressor signaling pathway. To date, it remains largely unclear as to how BLM and FA proteins work concurrently in the maintenance of genome stability. Here we report that BLM is involved in the early activation of FA group D2 protein (FANCD2). We found that FANCD2 activation is substantially delayed and attenuated in crosslinking agent-treated cells harboring deficient Blm compared to similarly treated control cells with sufficient BLM. We also identified that the domain VI of BLM plays an essential role in promoting FANCD2 activation in cells treated with DNA crosslinking agents, especially ultraviolet B. The similar biological effects performed by ΔVI-BLM and inactivated FANCD2 further confirm the relationship between BLM and FANCD2. Mutations within the domain VI of BLM detected in human cancer samples demonstrate the functional importance of this domain, suggesting human tumorigenicity resulting from mtBLM may be at least partly attributed to mitigated FANCD2 activation. Collectively, our data show a previously unknown regulatory liaison in advancing our understanding of how the cancer susceptibility gene products act in concert to maintain genome stability.
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